American Indians and Alaska Natives experience pervasive mental, behavioral, and physical health disparities, yet access to culturally relevant and evidenced-based programs (EBPs) are severely limited. The purpose of this research is to describe the process of conducting a rigorous and culturally sensitive research approach, which was used to inform the development of a family-based substance abuse and violence prevention program that promotes resilience. The focus of this article is on the process of this development, rather than the intervention itself. We utilize a convergent mixed-methods design with distinct tribes in the Southeast that included 436 research participants across individual, family, and focus group interviews, field notes and existing data, and a quantitative survey (n = 127). This community-engaged, culturally sensitive, and rigorous research methodology provides a road-map for developing culturally relevant interventions.